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Gene therapy for X-linked severe combined immunodeficiency (SCID)
Severe combined immunodeficiency (SCID) is a genetic disorder caused by non-functional T-cells. The humoral arm of the immune system is also affected in this disease due to the requirement of T-cells for activation of B-cells. The result is an immune system so severely compromised it is considered non- functional. (1) Individuals with SCID are extremely susceptible to all varieties of infection and usually die before the age of one without treatment. Worldwide estimates put the prevalence of SCID at around 1 in 100,000, though evidence exists that this figure is an under-estimate. Populations in which consanguineous breeding has been more common may experience SCID prevalence as high as 1 in 2,500. (2) Disruptions in at least nine different genes have been identified as leading to SCID. The most common gene mutation is in the gamma-c (or common gamma) light chain encoded by the IL-2 receptor gamma (IL-2Rg) gene located on the X-chromosome. (3) Gamma-c protein is required for the formation of several cytokine receptor complexes, including IL-2, -4, -7, -9, -15, and -21. Disruption of IL-2Rg leads to X-linked SCID as it is inherited in an X-linked recessive manner. (4) The current standard of care for X-linked SCID is to minimize challenges to the patient’s immune system in conjunction with a hematopoietic cell transplantation using a matched donor. Recently, the use of gene therapy to treat this disease has been explored, with clinical studies demonstrating the tremendous potential of this treatmentoption. (5) Gene therapy procedure Bone marrow is harvested from patients with X-linked SCID and enriched for hematopoietic stem cells (HSC) using anti cd34 antibodies. HSCs are then transduced in vitro using retroviruses containing a vector engineered to carry the gamma-c gene. Successfully transduced cells are selected for and reintroduced into the patient. Transduced cells begin to be detectable within a few weeks after plantation, though it usually takes around 6 months for the immune system to benefit from the procedure and to demonstrate normal function. (6) Clinical studies In a 2003 clinical trial in which 20 infants with X-linked SCID received retroviral gene therapy, 95% demonstrated successful engraftment of fully restored T cells. Furthermore, most sustained functional immune cells demonstrated by the ability to clear previously existing infections and the absence of any severe new infection. These results seemed to be limited to the treatment of infants, as a similar study involving patients age 10-20 years resulted in a successful transduced T-cell implantation in only 1 out of 5 subjects. However, the success observed in infants was overshadowed by the ~20% of patients later developing T-cell acute leukemia, caused by the insertion of retroviral DNA within an oncogene. (7,8) This is consistent with studies that have demonstrated that retroviruses preferentially insert into regions of high gene density, particularly at promoter regions. (9) Because of this, the US FDA enacted a moratorium in 2003 on any new clinical trials involving retroviral transduction of hematopoietic stem cells. The position of the FDA has since been amended to allow gene therapy on an individual basis if all other clinical strategies have proven ineffective. (6,10) Moving forward, refinement of the current transduction strategy is clearly needed for the full potential of gene therapy for X-linked SCID to be realized. Additionally, it is important for the limitation of the treatment for adolescents and young adults to be overcome to treat those currently suffering from this disease. References 1. International Union of Immunological Societies Expert Committee on Primary I, et al. (2009) Primary immunodeficiencies: 2009 update. The Journal of allergy and clinical immunology 124(6):1161-1178. 2. Verbsky J, Thakar M, & Routes J (2012) The Wisconsin approach to newborn screening for severe combined immunodeficiency. The Journal of allergy and clinical immunology 129(3):622-627. 3. Geha RS, et al. (2007) Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. The Journal of allergy and clinical immunology 120(4):776-794. 4. Noguchi M, et al. (1993) Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73(1):147-157. 5. Griffith LM, et al. (2009) Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. The Journal of allergy and clinical immunology 124(6):1152-1160 e1112. 6. Kohn DB (2010) Update on gene therapy for immunodeficiencies. Clinical immunology 135(2):247-254. 7. Sokolic R, Kesserwan C, & Candotti F (2008) Recent advances in gene therapy for severe congenital immunodeficiency diseases. Current opinion in hematology 15(4):375-380. 8. Chinen J & Puck JM (2004) Perspectives of gene therapy for primary immunodeficiencies. Current opinion in allergy and clinical immunology 4(6):523-527. 9. Hacein-Bey-Abina S, et al. (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. The New England journal of medicine 348(3):255-256. 10. Hacein-Bey-Abina S, et al. (2010) Efficacy of gene therapy for X-linked severe combined immunodeficiency. The New England journal of medicine 363(4):355-364.